Patiënten met een refractaire OAB of urge-incontinentie kunnen behandeld worden met intravesicale injecties met onabotulinumtoxin-A (BoNT-A) of met neuromodulatie. Patiënten met een refractaire OAB hebben nog steeds klachten ondanks conservatieve of medicamenteuze behandeling. Intravesicale injecties worden meestal poliklinisch toegediend middels een cystoscopie. De blaas wordt meestal voorbereid met een verdovende blaasspoeling. Bij percutane neuromodulatie (PTNS) en transcutane neurostimulatie (TENS) wordt elektrische stimulatie van de nervus tibialis aan de mediale zijde van de enkel gegeven. Bij sacrale neuromodulatie (SNM) wordt operatief een lead bij de sacrale zenuw, meestal S3, geplaatst. Alle behandelingen kennen specifieke voor- en nadelen. De uroloog kan samen met de patiënt beslissen welke behandeling het beste bij de situatie van de patiënt past, waarbij minder invasieve behandelingen voor meer invasieve behandelingen worden aangeboden.

1. Onabotulinumtoxin A versus SNM

1.1 Improvement/recovery of overactive bladder symptoms (critical)

Urgency incontinence episodes (BoNT-A 200IU versus SNM)

1.2 Quality of life (important)

1.3 Adverse events (important)

1.3.1 Cumulative urinary tract infection after 1 month

 1.3.2 Cumulative urinary tract infection after 3 months

 1.3.3 Cumulative urinary tract infection after 6 months

 1.3.4 Cumulative urinary tract infection between 7 and 12 months

 1.3.5 Cumulative urinary tract infection after between 13 and 24 months

 2. Onabotulinumtoxin A versus PTNS

2.1 Improvement/recovery of overactive bladder symptoms (critical)

2.2 Quality of life (important)

2.3 Adverse events, post-void residual (important)

 3. Onabotulinumtoxin A versus TENS

Description of studies

1. Onabotulinumtoxin A versus sacral neuromodulation (SNM)

Amundsen (2016) performed a multicenter randomized trial at nine sites. The study aimed to assess whether onabotulinumtoxin A 200IU (BoNT-A 200IU) was superior to sacral neuromodulation (SNM) in women with refractory urine incontinence symptoms. Women were included when they had at least six urgency incontinence episodes in three days at baseline (measured using a 3-day diary). Eligible patients had refractory urine incontinence defined as having symptoms despite at least one (physical/behavioral) intervention, and either failed previous interventions with at least two anticholinergics or were intolerant/contra- indicated for anticholinergics. Relevant neurologic disease, previous usage of either BoNT-A 200IU or SNM, or a post void residual of more than 150ml were criteria for exclusion. At randomization, 192 participants were randomized to receive BoNT-A 200IU. Due to invalid diary-data, 190 participants of the BoNT-A 200IU -group were included in the primary analysis. Initially, 194 participants were randomized to receive SNM. However, due to lead removals (n= 3), implanted pulse generator in non-responder (n= 9) and invalid diary-data (n= 5), 174 participants of the SNM-group were included in the primary analysis. Length of follow up was 6 months. Outcomes included intention to treat analyses on number of daily episodes, quality of life and adverse events. Patients were not blinded to assignment of treatment.

Amundsen (2018) presented the two-year follow-up outcomes for the trial by Amundsen (2016). All efficacy endpoints after two years were analyzed only in responders, which did not match the population described in the PICO. Adverse events after two years were analyzed per protocol in the original randomized population. In the BoNT-A 200IU -group, 191 participants were followed for adverse events. In the neuromodulation group, 178 participants were followed for adverse events.

2. Onabotulinumtoxin A versus posterior tibial nerve stimulation (PTNS)

Sherif (2017) performed a randomized controlled trial at one study site. The investigators opted to study the efficacy and safety of 100 IU Onabotulinumtoxin A (BoNT-A 100IU) (n=30) versus 12 weekly treatments with percutane tibial nerve stimulation (PTNS) (n=30) in patients with refractory idiopathic OAB. Refractory urine incontinence was defined as not responding or being intolerant to 3 months of medical therapy with different antimuscarinic agents. Having a pacemaker or implantable defibrillator, a current UTI, uncorrectable coagulopathies, a bladder outlet obstruction, a neurogenic bladder, a post void residual volume of >150 mL, planning to become pregnant or being pregnant, and nerve damage that might affect function of the posterior tibial nerve/pelvic floor were criteria for exclusion. Length of follow up was 9 months. Outcomes included intention to treat analyses on frequency (3-day voiding diary), quality of life and adverse events. Patients were not blinded to assignment of treatment.

3. Botox versus transcutaneous electrical nerve stimulation (TENS)

No studies were found for Botox versus TENS.

Table 1. Description of included studies

Results

1. Onabotulinumtoxin A versus SNM

1.1 Improvement/recovery of overactive bladder complaints (critical)

Amundsen (2016) reported on improvement of overactive bladder complaints in mean number of daily episodes measured for 3 consecutive days every month, over 6 months measured with a 3-day bladder diary. In the BoNT-A 200IU group (n= 190), the adjusted mean number of daily urgency urinary incontinence episodes reduced with -3.89 (95% CI -4.26 to -3.52). In the SNM group (n= 174), adjusted mean number of daily urgency urinary incontinence episodes reduced with -3.25 (95% CI -3.64 to -2.87). The adjusted mean difference was 0.63 (95% CI: 0.13 to 1.14). This difference was not clinically relevant.

1.2 Quality of life (important)

Amundsen (2016) reported on quality of life using the Overactive Bladder Questionnaire Short Form (OABq-SF, range 0-100, higher scores indicate higher quality of life). Other quality of life questionnaires were completed (Urinary Distress Inventory short form (UDI-SF), Incontinence Impact Questionnaire short form (IIQ-SF) and Health Utility Index (HUI-3)), but defined as secondary endpoints. In the BoNT-A 200IU (n= 190), the mean score at 6 months was 41.6 (SD 25.9). In the SNM-group (n= 174), the mean score was 38.1 (SD 26.7). The mean difference was 3.5 (95% CI -1.91 to 8.91). This difference was not clinically relevant.

1.3 Adverse events (important)

Adverse events were measured up to six months after baseline and were defined as urinary tract infection. Amundsen (2016) reported on cumulative urinary tract infections after one month, three months and six months. Amundsen (2018) reported on urinary tract infections between 7 and 12 months and between 13 and 24 months. Results are presented in table 2. All differences were clinically relevant favoring the SNM-group.

No results were reported for device related pain.

Table 2. UTI’s reported by Amundsen (2016)

Amundsen (2016) used intermittend catheterization as a proxy for urinary retention (defined as a residual >300mL/ >200mL with symptoms of incomplete voiding). In the BoNT-A 200IU group, 38 out of 191 participants required intermittend self-catheterization. No results were reported for the SNM group, thus these results were not graded.

In the SNM group, in 6 out of 174 patients the device was removed or revised. Also, for this outcome, results were not graded since patients in the BoNT-A 200IU group were not at risk for device removal/revision.

Level of evidence of the literature

1.1  Improvement/recovery of overactive bladder complaints (critical)

The level of evidence regarding the outcome measure incontinence episodes started as high because it was based on an RCT and was downgraded by three levels to very low because of unbalanced dropout and lack of blinding (-2, risk of bias); and low number of included patients (-1, imprecision).

1.2  Quality of life (important)

The level of evidence regarding the outcome measure quality of life started as high because it was based on an RCT and was downgraded by three levels to very low because of unbalanced dropout and lack of blinding (-2, risk of bias) and number of included patients (-1, imprecision).

1.3  Adverse events/complications (important)

1.3.1 Urinary tract infections (1-month post-intervention)

The level of evidence regarding the outcome measure AE after 1 month started as high because it was based on an RCT and was downgraded by two levels to low because of unbalanced drop-out (-1, risk of bias) and low number of included patients (-1 imprecision).

1.3.2 Cumulative urinary tract infections (up to 3 months post-intervention)

The level of evidence regarding the outcome measure AE after 3 months started as high because it was based on an RCT and was downgraded by two levels to low because of unbalanced drop-out (-1, risk of bias) and low number of included patients (-1 imprecision).

1.3.3 Cumulative urinary tract infection (up to 6 months post-intervention)

The level of evidence regarding the outcome measure AE after 6 months started as high because it was based on an RCT and was downgraded by two levels to low because of unbalanced drop-out (-1, risk of bias) and low number of included patients (-1 imprecision).

1.3.4 Urinary tract infections 7-12 months

The level of evidence regarding the outcome measure AE between 7 and 12 months started as high because it was based on an RCT and was downgraded by two levels to low because of unbalanced drop-out (-1, risk of bias) and low number of included patients (-1 imprecision).

1.3.5 Urinary tract infections 13-24 months

The level of evidence regarding the outcome measure AE between 13 and 24 months was downgraded by two levels to low because of unbalanced drop-out (-1, risk of bias) and low number of included patients (-1 imprecision).

2. Onabotulinumtoxin A 100 IU (BoNT-A 100IU) versus 12 weekly treatments with PTNS

2.1 Improvement/recovery of overactive bladder complaints (critical)

Sherif (2015) reported on leaking episodes using a 3-day voiding diary. In the BoNT-A 100IU -group (n= 29), the mean score at 9 months was 3.5 (SD 1.2). In the PTNS-group (n= 28), the mean score was 4.2 (SD 1.04). The mean difference was 0.30 (95% CI -0.28 to 0.88). This difference was not clinically relevant.

2.2 Quality of life (important)

Sherif (2017) reported on quality of life using the Overactive Bladder Symptom Score (OABSS), range 0-4, higher scores indicate lower quality of life) quality of life scale. In the BoNT-A 100IU group (n= 29), the mean score at 9 months was 2.6 (SD 0.6). In the PTNS-group (n= 28), the mean score was 2.9 (SD 0.6). The mean difference was -0.3 (95% CI -0.61 to 0.01). This difference was not clinically relevant.

2.3 Adverse events (important)

Sherif (2017) reported on post-void residual, using a 3-day voiding diary. In the BoNT-A 100IU -group (n= 29), the mean post-void residual at 9 months was 36.8 mL (SD 2.7). In the PTNS-group (n= 28), the mean post-void residual was 32.4 mL (SD 3.04). The mean difference was 4.40 mL (95% CI 2.91 to 5.89). This difference was not clinically relevant, favoring the PTNS-group.

Level of evidence of the literature

2.1 Improvement/recovery of overactive bladder complaints (critical)

The level of evidence regarding the outcome measure leaking episodes started as high because it was based on an RCT and was downgraded by three levels to very low because of lack of blinding, poor description of analysis, lack of protocol-registration and other methodological shortcomings (-2, risk of bias); and low number of included patients (-1, imprecision).

2.2 Quality of life (important)

The level of evidence regarding the outcome measure quality of life started as high because it was based on an RCT and was downgraded by three levels to very low because of lack of blinding and methodological shortcomings (-2, risk of bias); and confidence interval overlap with threshold of clinical decision-making (-1 imprecision).

2.3 Adverse events/complication (important)

The level of evidence regarding the outcome measure adverse events started as high because it was based on an RCT and was downgraded by three levels to very low because of lack of blinding and methodological shortcomings (-2, risk of bias); and low number of included patients (-1, imprecision).

A systematic review of the literature was performed to answer the following question: What is the effectiveness and safety of intravesical injection of botulinum toxin (type A or B) compared with neuromodulation for patients with refractory overactive bladder?

P: Adults with refractory overactive bladder.

I: Intravesical injection of botulinum toxin (type A or B).

C: Neuromodulation (sacral nerve stimulation (SNM); percutaneous tibial nerve stimulation (PTNS); transcutaneous nerve stimulation (TENS).

O: Improvement/recovery of overactive bladder complaints, quality of life, adverse events/complications.

Relevant outcome measures

The guideline development group considered improvement/recovery of overactive bladder as a critical outcome measure for decision making; and quality of life and adverse events/complications as an important outcome measure for decision making.

A priori, the working group defined adverse events as (recurrent) urinary tract infection, post void residual, urinary retention, and device related pain. For other outcomes, the working group did not define the outcome measures listed above but used the definitions used in the studies.

The working group defined the following minimal clinically (patient) important differences:

Continuous outcomes:

• Improvement/recovery of overactive bladder complaints
  • Three-day diary: ≥ 50% reduction (Schmidt, 1990)
  • Urinary Distress Inventory (UDI-6, 0-100): ≥ 33.33 (Skorupska, 2021)
  • International Consultation on Incontinence Modular Questionnaire – Urinary incontinence (ICIQ-UI): ≥ 0.5 SD
  • International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OAB): ≥ 0.5 SD
• Quality of life:
  • International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF, 0-21): ≥ 5 at 12 months, ≥ 4 at 24 months (Sirls, 2013)
  • The overactive bladder questionnaire (OAB-q, 0-100): ≥ 10 points (Coyne, 2006)
  • The overactive bladder quality of life short-form questionnaire (OAB-q SF, 0-100): ≥ 11 points (Blanker, 2019)

In all other cases, the working group defined the GRADE-standard limit of 25% difference for dichotomous outcomes (RR < 0.8 or > 1.25), and 0.5 SD for continuous outcomes as a minimal clinically (patient) important difference.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2000 until 3 January 2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 92 hits. Studies were selected based on the following criteria:

• Systematic review (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available), randomized controlled trial or observational study comparing intravesical injection of botulinum toxin (type A or B) with neuromodulation (sacral nerve stimulation (SNM); percutaneous tibial nerve stimulation (PTNS); transcutaneous nerve stimulation (TENS);
• Patients aged ≥ 18 years;
• Full-text English language publication;
• Studies including ≥ 20 (ten in each study arm) patients; and
• Studies according to PICO.

A total of 15 studies were initially selected based on title and abstract screening. After reading the full text, 12 studies were excluded (see the table with reasons for exclusion under the tab Methods), and three studies were included (Amundsen, 2016; Amundsen, 2018 and Sherif, 2015). One systematic review matched the predefined PICO (He, 2021). This review reported on a randomized controlled trial (with outcomes described in two relevant publications; Amundsen, 2015 and Amundsen, 2018)), and three low quality cohort studies. Since the quality of these cohort studies was not sufficient, the review was not included.

Results

Three studies were included in the analysis of the literature (Amundsen, 2016; Amundsen, 2018 and Sherif, 2015). Important study characteristics and results are summarized in table 1 and the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.